Closed vial fill system for aseptic dispensing

ABSTRACT

A closed path vial fill system includes a bulk product vial, a peristaltic pump operated by a stepper motor, a dispensing manifold assembly to which may be coupled at least one final product vial, an optional quality check station, and an optional waste collection system. A concentration, activity, and volume (CAV) sensor may be incorporated into the system to receive a radiopharmaceutical product directly from a synthesizing unit. A control system may be integrated into the system to provide automated control of various aspects of the radiopharmaceutical dispensing process. The system is used to aseptically dispense finished radiopharmaceuticals into receiving vessels, such as a Quality Control vial, a sterility vial, and/or final product vials, while providing users an efficient means for removing and discarding contaminated disposable components.

This application is a continuation of U.S. patent application Ser. No.13/339,226 entitled “CLOSED VIAL FILL SYSTEM FOR ASEPTIC DISPENSING”filed on Dec. 28, 2011 and issued as U.S. Pat. No. 9,139,613, whichclaims priority to U.S. Provisional Patent Application No. 61/428,041entitled “CLOSED VIAL FILL SYSTEM FOR ASEPTIC DISPENSING” filed on Dec.29, 2010, and to U.S. Provisional Patent Application No. 61/508,409entitled “CLOSED VIAL FILL SYSTEM FOR ASEPTIC DISPENSING” filed on Jul.15, 2011, the entirety of each is incorporated by reference herein.

BACKGROUND OF THE INVENTION

Field of the Invention

Aspects of the present invention relate generally to a vial fillingsystem and methods of use thereof. More specifically, particular aspectsof the invention relate to a device for filling vials with measuredquantities of a substance or substances, for use in the diagnosticimaging field of nuclear medicine.

Description of Related Art

Positron Emission Tomography (PET) is a nuclear medicine imagingtechnique in which a positron-emitting radionuclide, such as carbon-11,nitrogen-13, oxygen-15 or fluorine-18, is chemically incorporated into acompound normally used by the body, such as glucose, water or ammonia.The compound may then be injected into a patient, for example, so that atargeted biological process of the body will naturally distribute thecompound. The radionuclide serves as a tracer for subsequent imaging bya scanner, wherein the decay of the radioisotope produces a record ofthe concentration of the tissue in the area being imaged, providing apractitioner detailed views of a targeted anatomy in a patient whencombined with a Computerized Tomography (CT) study (CT/PET).

Nuclear medicine requires special considerations in the preparation,handling and delivery of radioactive materials for use in variousmedical procedures. For example, fluorodeoxyglucose (FDG), an analogueof glucose, is commonly used for the chemical incorporation of theradioisotope fluorine-18 for use in PET procedures. Production of theradioisotope fluorine-18 for use in the radiopharmaceutical is oftendifficult and/or expensive, requiring specialized equipment such as acyclotron. Thus, the production of the radioisotope often occurs at aremote facility by a third party, from which the hospital or labreceives patient doses ready to inject. Even if the radioisotope happensto be produced on site, final production of the radiopharmaceuticalsused in many diagnostic imaging procedures requires manual preparationin a special aseptic environment to ensure a safe injectable productfree of environmental contaminants and for precise accounting of theradioactive nature of the radionuclide to be used in theradiopharmaceutical for each procedure, recognizing that the bulkradionuclide product is continuously decaying over time. Furthermore,during preparation of the radiopharmaceutical, the radiopharmacists mustbe shielded from the ionizing radiation of the radioisotope, and thepurity of the radiopharmaceutical must be ensured by filtering and/oravoiding contamination through contact with particles in the air, on asurface, and/or when mixing with a diluting liquid, for example. Thus,because of the short half-life of the radionuclide, the efficientscheduling of patients, for example, along with a safe and efficientpreparation of the radiopharmaceutical by technicians is critical inorder to avoid wasting the prepared bulk product of the radionuclide.

To create an aseptic environment for the production of pharmaceuticals,a special clean air “canopy” or laminar flow hood, for example, is oftenused, wherein high-efficiency particulate air (HEPA) filters areprovided in conjunction with a closed containment structure, withinwhich the pharmaceuticals can be prepared. The interior environment ofthe containment structure is closely monitored, for example, by aparticle counter, to determine the airborne particulate density ofpossible contaminates. However, when preparation of the pharmaceuticalincludes a radioactive material, the aseptic environment described abovemust also be shielded. It is very difficult to combine a shieldedenclosure with a filtered environment without compromising the abilityto produce a radiopharmaceutical compound efficiently.

Furthermore, present procedures for dispensing radiopharmaceuticals intofinal product vials for delivery to one or more patients often involvesaccessing and extracting the radionuclide product for an individualprocedure from a bulk product vial. The bulk product vial may alreadycontain other components, such as sterile water for injection of theradioactive component, or other components may be added to the bulkproduct vial as necessary or contained/added to each individual vial formixing with the radionuclide. The bulk product vial, which is containedin a shielded enclosure to minimize exposure of the technician toradiation, is typically accessed by one or more technicians using asyringe to puncture a resealable membrane of the bulk product vial inorder to extract a quantity of the radioactive component. Thus, eachtime a quantity of the radioactive component is extracted in thismanner, there is a chance that contaminants can be introduced into thebulk product vial as the syringe punctures and/or is removed from thebulk product vial.

To decrease the chance of contamination by multiple punctures of asyringe, it has been proposed to use an automated syringe thatautomatically draws material from the bulk product vial into each of theindividual vials. However, even if a syringe pump, for example, reducesthe chance of contamination by reducing the number of times the bulkproduct vial membrane is punctured, each plunge of the syringe after theinitial plunge risks contamination through airborne particles, forexample, being drawn in through the back of the syringe.

Thus, the use of syringes in the preparation of a radiopharmaceuticalhas inherent drawbacks in preserving the quality and accuracy of a doseto be dispensed for use in a medical procedure, for example.Additionally, syringes can limit the size of a dose being dispensed. Forexample, when the goal is to withdraw the product from the bulk productvial with one plunge in order to reduce the risk of contamination, arequirement for a 100 ml dose of a product would require the use of anunusually large syringe.

Accordingly, there is a need for a system and associated methods forproviding an aseptic, closed path vial fill system that may overcome oneor more of the problems discussed above. In particular, there is a needfor improved vial filling systems that may promote a more efficientsetup and procedure for dispensing radiopharmaceuticals in a safe andeffective manner that guarantees the integrity of theradiopharmaceutical every time.

SUMMARY OF THE INVENTION

In accordance with aspects of the present invention, a closed path vialfill system may include a bulk product vial, a peristaltic pump operatedby a stepper motor, a dispensing manifold assembly to which may becoupled to at least one final product vial, an optional quality checkstation, and an optional waste collection system. A control system maybe integrated into the system to provide automated control of variousaspects of the radiopharmaceutical dispensing process. The system isused to aseptically dispense finished radiopharmaceuticals from a bulkproduct vial into receiving vessels, such as a Quality Control syringe,a sterility vial, and/or final product vials.

Additional features of various exemplary implementations of theinvention will be set forth in part in the description which follows. Itwill become readily apparent to those skilled in the art from thefollowing detailed description, wherein it is shown and described onlyin exemplary configurations of a closed vial fill system, thatvariations of the invention may include other and different aspects of aclosed vial fill system capable of modification in various otherrespects, all without departing from the spirit and scope hereof.Accordingly, the drawings and the detailed description are to beregarded as illustrative in nature and not as restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate various exemplary implementationsconsistent with aspects of the invention, and, together with thedescription, serve to explain the principles thereof.

FIG. 1 is an illustration of a closed path vial fill system, inaccordance with certain aspects of the present invention;

FIG. 2 is another illustration of the closed path vial fill system ofFIG. 1, in accordance with certain aspects of the present invention;

FIG. 3 is another illustration of the closed path vial fill system ofFIG. 1, in accordance with certain aspects of the present invention;

FIG. 4 is an illustration of an in-situ filter testing assembly, inaccordance with certain aspects of the present invention;

FIG. 5 is a pressure graph to illustrate aspects of the in-situ filtertesting assembly, in accordance with certain aspects of the presentinvention;

FIG. 6 is a perspective view of a partially assembled closed path vialfill system, in accordance with certain aspects of the presentinvention;

FIG. 7 is a top perspective view of a partially assembled closed pathvial fill system, in accordance with certain aspects of the presentinvention;

FIG. 8 is a front view of aspects of a partially assembled closed pathvial fill system, in accordance with certain aspects of the presentinvention;

FIG. 9 is an illustration of aspects of a closed path vial fill systemhaving an in situ sterility testing system, in accordance with certainaspects of the present invention;

FIG. 10 is an illustration of a sterile kit assembly for use with aclosed path vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 11 is a top view of a packaged sterile kit assembly for use with aclosed path vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 12 is a perspective view of an exemplary vented fill cap, inaccordance with certain aspects of the present invention;

FIG. 13 is a top view of a vial with a pierced septum, in accordancewith certain aspects of the present invention;

FIG. 14 is a perspective view of a packaging device for use with avented fill cap and a vial, in accordance with certain aspects of thepresent invention;

FIG. 15 is a perspective view of the packaging device of FIG. 14 shownin a position of use, in accordance with certain aspects of the presentinvention;

FIG. 16 is a perspective view of a packaging device for use with avented fill cap and a vial, in accordance with certain aspects of thepresent invention;

FIG. 17 is a perspective view of the packaging device of FIG. 16 shownin a position of use, in accordance with certain aspects of the presentinvention;

FIG. 18 is a perspective view of a packaging device for use with avented fill cap and a vial, in accordance with certain aspects of thepresent invention;

FIG. 19 is a perspective view of the packaging device of FIG. 18 in astate of use, in accordance with certain aspects of the presentinvention;

FIG. 20 is a perspective view of the packaging device of FIG. 18 shownin a position of use, in accordance with certain aspects of the presentinvention;

FIG. 21 is a perspective view of a sterile packaging of a sterile kit ofdisposable elements for use in a closed path vial fill system, inaccordance with certain aspects of the present invention;

FIG. 22 is an illustration of a vial fill procedure in accordance withcertain aspects of the closed path vial fill system of FIG. 1;

FIG. 23 is another illustration of the closed path vial fill system ofFIG. 1, in which multiple vial sizes are used, in accordance withcertain aspects of the present invention;

FIG. 23A is an illustration of a branched multiple vial connection, inaccordance with certain aspects of the present invention;

FIG. 24 is an illustration of a vial evacuation procedure in accordancewith certain aspects of the closed path vial fill system of FIG. 1;

FIG. 25 is an illustration of a vial pressurization procedure inaccordance with certain aspects of the closed path vial fill system ofFIG. 1;

FIG. 26 is another illustration of the closed path vial fill system ofFIG. 1, wherein the vials are each filled, in accordance with certainaspects of the present invention;

FIG. 27 is another illustration of the closed path vial fill system ofFIG. 1, wherein the vials are released from the dispensing manifolds, inaccordance with certain aspects of the present invention;

FIG. 28 is an illustration of a system flushing process in accordancewith certain aspects of the closed path vial fill system of FIG. 1,

FIG. 29 is an illustration of a closed path vial fill system in ashielded enclosure, in accordance with certain aspects of the presentinvention;

FIG. 30 shows various features of an example computer system for use inconjunction with aspects of a closed path vial fill system, inaccordance with aspects of the present invention;

FIG. 31 shows an exemplary flow diagram of various functions performedin a system and method for controlling aspects of a closed path vialfill system, in accordance with aspects of the present invention;

FIG. 32 is an exemplary screenshot of a software interface for automatedcontrol of various functions of a closed path vial fill system, inaccordance with aspects of the present invention;

FIG. 33 shows an exemplary closed path vial fill system incorporating aCAV sensor, in accordance with certain aspects of the present invention;

FIG. 34 is a side view of the exemplary closed path vial fill system ofFIG. 33, in accordance with certain aspects of the present invention;

FIG. 35 is an illustration of a bracket for mounting a bulk productvial, in accordance with certain aspects of the present invention;

FIG. 36 is another illustration of an exemplary closed path vial fillsystem incorporating a CAV sensor, in accordance with certain aspects ofthe present invention;

FIG. 37 is a schematic of an exemplary closed path vial systemincorporating a CAV sensor, in accordance with certain aspects of thepresent invention;

FIG. 38 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 39 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 40 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 41 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 42 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 43 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 44 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 45 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 46 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 47 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 48 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 49 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 50 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 51 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 52 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 53 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 54 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 55 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 56 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 57 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 58 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 59 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 60 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 61 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 62 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 63 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention;

FIG. 64 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention; and

FIG. 65 is a schematic diagram to illustrate exemplary aspects of aclosed vial fill system incorporating a CAV sensor and a method of usingthe closed vial fill system, in accordance with certain aspects of thepresent invention.

DETAILED DESCRIPTION

Various aspects of a closed path vial fill system may be illustrated bydescribing components that are coupled, attached, and/or joinedtogether. As used herein, the terms “coupled”, “attached”, and/or“joined” are interchangeably used to indicate either a direct connectionbetween two components or, where appropriate, an indirect connection toone another through intervening or intermediate components. In contrast,when a component is referred to as being “directly coupled”, “directlyattached”, and/or “directly joined” to another component, there are nointervening elements shown in said examples.

Relative terms such as “lower” or “bottom” and “upper” or “top” may beused herein to describe one element's relationship to another elementillustrated in the drawings. It will be understood that relative termsare intended to encompass different orientations of a closed path vialfill system in addition to the orientation depicted in the drawings. Byway of example, if aspects of a closed path vial fill system shown inthe drawings are turned over, elements described as being on the“bottom” side of the other elements would then be oriented on the “top”side of the other elements as shown in the relevant drawing. The term“bottom” can therefore encompass both an orientation of “bottom” and“top” depending on the particular orientation of the drawing.

Various aspects of a closed path vial fill system may be illustratedwith reference to one or more exemplary implementations. As used herein,the term “exemplary” means “serving as an example, instance, orillustration,” and should not necessarily be construed as preferred oradvantageous over other variations of the devices, systems, or methodsdisclosed herein.

As shown in FIG. 1, an exemplary closed path vial fill system 10 mayinclude a bulk product vial 100, a peristaltic pump 200, a dispensingmanifold assembly 300 to which may be coupled at least one final productvial 400, a sterility vial 450, an optional quality check station 480,and an optional waste collection system 600. A control system 700 (e.g.,see FIG. 27) may be integrated into the system 10 to provide automaticand/or manual control over various aspects of the radiopharmaceuticaldispensing process. Although described herein as having one pump 200 orone bulk product vial 100, for example, the system may encompassmultiple pumps feeding multiple fluid pathways for dispensing multipledifferent products without cross contamination. The potential exposureof technicians may be further reduced, as the necessity to enter theshielded environment in order to change out disposable components of thesystem 10 between batches (radiation safety hazard) may be furtherreduced.

As shown in FIG. 1, the peristaltic pump 200 may be a simple mechanicalpump comprising a replaceable tube element 210 and rollers 220, forexample. The rollers 220 are conventionally provided at intervals alonga radial track and rotate about a central axis to exert localizedpressure on the tube element 210, which in turn pushes a fluid throughthe tube element 210 and creates a negative pressure at an inlet of thetube element 210 for drawing additional fluid into the tube element 210.Control of the fluid flow may be by way of a standard motor (not shown)coupled to the peristaltic pump 200. However, as shown in FIG. 1, byattaching a stepper motor 250, for example, to the peristaltic pump 200,aspects of the present invention permit a much more refined degree ofcontrol over the fluid flow parameters through the tube element 210. Forexample, by calibrating the rotation of the pump 200 in accordance withthe rotation of the stepper motor 250, as determined by a number ofpulses applied by the stepper motor 250 over a given period of time, acontrol algorithm may be determined to accurately predict and controlthe amount of fluid being pushed through the tube element 210 as afunction of the number of pulses of the stepper motor 250.

In accordance with another aspect of the invention, the control system700 may be used to store calibration data for each position of a finalproduct vial 400 along the dispensing manifold assembly 300, permittingvery precise control of the fluid flow parameters into each finalproduct vial 400 without the need for individual flow meters for eachfinal product vial 400. Although referred to herein as a final productvial 400, the final product vial 400 may be any suitable vessel forreceiving a quantity of the radiopharmaceutical product, including asterility vial, final product vial, or a quality control syringe, forexample.

According to another aspect of the present invention, the stepper motor250 may be used to operate the peristaltic pump 200 in reverse. As such,the closed path vial fill system 10 may be used to draw a dilutingsolution, such as a sterile saline solution, from a dilution container260, for diluting the bulk radionuclide product in the bulk product vial100. The dilution container 260 may be a flexible, sterile bag comprisedof a resilient PVC material, for example. As shown in FIG. 1, thedilution container 260 may be integrated into the system 10, preferablybetween the peristaltic pump 200 and the dispensing manifold assembly300, by way of a valve 265. The valve 265 may be a three-port solenoidvalve, a diverter valve, or a stopcock valve, for example, and providesclosed fluid communication between the peristaltic pump 200 and thedispensing manifold assembly 300 when selectively actuated to a firstposition, and closed fluid communication between the dilution container260 and the peristaltic pump 200 when selectively actuated to a secondposition.

As shown in FIG. 2, for example, a typical deposit of the bulkradiopharmaceutical product 110 may include a select amount of theradiopharmaceutical product 110, such as FDG (fluorodeoxyglucose) orFMISO (fluoromisonidazole), for example, delivered from a chemistrysynthesis unit (CSU) through a section of tubing 120, an air eliminatingfilter (AEF) 122, and a sterilizing filter 124, such as a 0.2 μm liquidfilter, into the bulk product vial 100. A filtered vent needle 130 maybe provided to vent the interior of the bulk product vial 100 as theradiopharmaceutical product 110 is loaded into the bulk product vial100. An aspirating needle 144, for example, may be used to puncture theseptum of the bulk product vial 100 for connection to the tube element210, such as by way of a luer lock, for example (see also FIG. 10). Withthe aspirating needle 144 inserted to place an intake near a bottomsurface of the bulk product vial 100, the dispensing manifold assembly300 is placed in fluid communication with the bulk product vial 100 topull substantially all of the bulk product from the bulk product vial100. The bulk product vial 100 may be enclosed by a shielded box, 140,and a well counter (not shown), for example, or any suitable dosecalibrator, may be provided to assay the radioactivity level of thedeposited bulk radiopharmaceutical product 110 in the bulk product vial100. In accordance with the measured radioactivity level of thedeposited bulk radiopharmaceutical product 110, the stepper motor 250may be activated to operate the peristaltic pump 200 in reverse toprovide a predetermined amount of the dilution solution to the bulkproduct vial 100.

As shown in FIG. 3, with the valve 265 closed to the dispensing manifoldassembly 300 and open to the dilution container 260, the stepper motor250 may be controlled to operate the pump 200 for a predetermined timeto deliver the predetermined amount of dilution solution into the bulkproduct vial 100. The control system 700 may be used to storecalibration data with respect to an initial void of fluid in the pump200 when the stepper motor 250 is initially activated. For example, byaccounting for the dimensions of the tube element 210, the system 10 maybe controlled to deliver a precise amount of dilution solution from thedilution container 260 into the bulk product vial 100, accounting forthe initial volume of air in the tube element 210. In accordance withanother aspect of the present invention, a fluid sensor may be providedat a specific point near the entrance and/or exit of the peristalticpump 200, so that specific stepper motor control over the fluid flowthrough the pump is not initiated until the fluid sensor senses a liquidflow, indicating the pump has cleared any air in the tube element 210.With the deposited radiopharmaceutical product 110 in the bulk productvial 100 thus diluted for injection, the valve 265 may be closed to thedilution container 260 and opened to the dispensing manifold assembly300 for extracting the diluted solution from the bulk product vial 100and dispensing the radiopharmaceutical solution into the individualfinal product vials 400 for use in a procedure.

As shown in FIGS. 1-3, the dispensing manifold assembly 300 may includeone or more central manifold tubes 310. Each central manifold tube 310may include a central flow tube and a number of dispensing ports 312 fordispensing an injection solution into an individual vial 400. Inaccordance with another aspect of the present invention, each end of themanifold tube 310 may include a connecting means 314, such as a luerconnection, or an externally threaded end, for example, for secureattachment of tubes, connectors, and/or another manifold tube 310, topermit efficient expansion of the system 10, if desired. Althoughdepicted in FIGS. 1-3 as having two manifold tubes 310, with eachmanifold tube 310 having five dispensing ports 312 in a lineararrangement, the system 10 may include one or more manifold tubes 310,with each manifold tube 310 having one or more dispensing ports 312. Inaccordance with yet other aspects of the present invention, the system10 may be configured to provide the dispensing ports 312 in a variety ofarrangements. For example, the manifold tubes 310 may be formed in acircular shape, or a y-connector and valve assembly may be used toprovide multiple manifold tubes 310 in a parallel arrangement. Themanifold tubes 310 may be formed from any suitable high-strength, hardplastic, such as nylon, polypropylene, polycarbonate and/orpolyvinylidene fluoride (PVDF), which allows sterilization of the tubes310, such as by steam sterilization or gamma radiation sterilization,and easy removal and disposal of the manifold tubes 310 after eachdispensing run, for example.

Valves 320, such as three-port solenoid valves, for example, may beprovided at the junction of each dispensing port 312 and the manifoldtube 310. Each valve 320 may be selectively actuated between multipleoperational positions, including a first valve position, which shuts offfluid flow to the dispensing port 312 and allows unimpeded,substantially laminar fluid flow through the manifold tube 310, and asecond valve position, which diverts the fluid flow in the manifold tube310 toward the dispensing port 312 associated with the valve 320. Eachvalve 320 may be pneumatically, hydraulically, and/or electricallyactuated between operational positions, and control may be automatedthrough the control system 700. In this manner, each valve 320 may beprovided with a dedicated control motor, for example, or a single sourceof power may be provided to actuate all valves 320.

As shown in FIGS. 1-3, a sterilization filter 270, such as a 0.22 micronantimicrobial filter, may be provided between the valve 265 and thedispensing manifold assembly 300. Alternatively, the filter 270 may belocated prior to the pump 200, or in any location along the closed pathbetween the bulk product vial 100 and the vials 400. Any of theradiopharmaceutical products intended for dispensing into a finalproduct vial 400 must pass through the sterilization filter 270, whichis required by government regulation to ensure the integrity of thefinal radiopharmaceutical product planned for injection into a subject.Furthermore, the integrity of the sterilization filter 270 must betested and verified following use in the system 10.

Aspects of the present invention may optionally include an in-situfilter integrity testing system. Normally, following the dispensingprocess, a technician must dismantle and remove the filter from thedispensing system to apply a nitrogen pressure test to the filter as anintegrity test. The procedure may introduce additional exposure risk tothe technician. The in-situ filter integrity testing system of thepresent invention includes a pressurized gas line 275 that may beconnected through a diverter valve 280, for example, to enter the fluidflow path on a downstream side of the sterilization filter 270, betweenthe filter 270 and the first manifold assembly 310. As shown in FIG. 4,in-situ filter integrity testing may be provided by opening the divertervalve 280 to allow pressurized gas, preferably nitrogen gas, to flowfrom the pressurized line 275 upstream toward the sterilization filter270. As shown in FIG. 5, a pressure on the downstream side of thesterilization filter 270 will presumably increase until the filterfails, such as by puncture failure of a diaphragm element 272, forexample. Any suitable pressure sensor may be provided to record thepressure on the downstream side of the filter 270. Because a failurepressure (i.e., bubble point) has been predetermined for the filter 270,which may be in the range of 40-50 psi for a typical 0.22 micron filter,for example, as long as the pressure on the downstream side of thefilter increases as expected to a minimum threshold value, the test maybe considered a success and the integrity of the filter 270 validated.However, if the pressure on the downstream side of the filter 270 failsto increase as expected, or increases but fails to reach the minimumthreshold value, the test may reveal a failure in the filter 270 and theintegrity of the dispensed radiopharmaceutical products may be suspect.The filter 270 may then be removed from the system 10, for example, andretested to verify the results.

According to another aspect of the present invention, in-situ filterintegrity testing may be provided by installing a suitable gas flowdetector element on the upstream side of the filter 270, i.e., the sideclosest to the pump 200. Accordingly, when the downstream side of thefilter 270 is pressurized by opening of the diverter valve 280, if thegas flow detector senses any gas flow, or a gas flow through the filter270 above a minimum flow threshold, for example, the filter 270 may bedetermined to have failed the integrity test and the radiopharmaceuticalproduct dispensed through the filter declared suspect. Additionaltesting on the filter and/or dispensed product may be ordered todetermine if the product may be contaminated or is safe for injection.

The system 10 may be set up as shown in FIGS. 6-8. A frame 40, which maybe a hollow parallelepiped constructed from aluminum, for example, maybe provided for mounting the various structural and disposable elementsof the system 10. For example, the peristaltic pump 200 may be securelymounted toward one side of the frame 40. The stepper motor 250 may beintegrated with the pump 200 or mounted to an interior portion of theframe 40. As shown in FIG. 6, the pump 200 may have a cover 202 thatopens for access to an interior compartment and the rollers 220. Asshown in FIGS. 7 and 8, the tube element 210 may be inserted into thepump 200 between the rollers 220 and an outer race so that both ends ofthe tube element 210 extend from the pump 200. As shown in FIG. 8, oneend of the tube element 210 connects to the filter 270 which, in turn,connects to the manifold tube 310 of the dispensing manifold assembly300. The other end of the tube element 210 may be connected to the bulkproduct vial 100 by any suitable means to ensure that the suctionpressure of the pump 200 will draw product from the bulk product vial100 into the tube element 210.

The rotary actuators that control the rotary motion of the valves 320may be mounted through mounting holes provided in the frame 40. As shownin FIG. 8, the manifold tubes 310 may be mounted so that the rotaryactuators selectively actuate each of the valves 320. The final productvials 400 may then be attached to each of the dispensing ports 312, asnecessary, in preparation for a dispensing run As described below ingreater detail, the final product vials 400 may be attached to thedispensing ports 312 in an aseptic environment prior to mounting on thechassis of the manifold assembly. Each vial 400 may be directlyconnected to a dispensing port 312 or connected via a connector tube412, for example. As shown in FIG. 8, vial caps 420, such as vented fillvial caps, may be provided with each vial 400 for connection to adispensing port 312. The fill caps 420 provide a sealed disconnect sothat the vials 400 may be removed from the system 10 without externalexposure to the radiopharmaceutical contained therein.

As shown in FIGS. 1-3, the system 10 may include a quality check station480. Although depicted as a separate element attached to a distal end ofa manifold tube 310, the quality check station may simply include asyringe or quality check vial 482 connected to one of the dispensingports 312, as shown in FIG. 10, for receiving a quantity of thedispensed radiopharmaceutical product. Thus, a sample of theradiopharmaceutical product being dispensed into the vials 400 may beretrieved for appropriate testing of purity, clarity, and the safety ofthe product. For example, an FDG product may be checked to ensure it isfree of particulates, is the right pH, and/or contains an appropriateconcentration of active radionuclide.

In accordance with another aspect of the present invention, one or moreof the final product vials 400, containing a representative quantity ofdispensed radiopharmaceutical, may be identified as a sterility vial450, wherein the sterility vial 450 may be removed from the system 10and the contents subjected to sterilization testing using a culturemedium, for example, to determine if the radiopharmaceutical had beencompromised during the compounding and/or dispensing process.

In another aspect according to the present invention, an in situsterility test may provide an additional built in quality check for theclosed vial fill system 10. Typically, a small volume sample of theradiopharmaceutical may be drawn into a syringe from a final productvial 400, for example, and then dropped into a growth media. By using asterility vial 450 already containing a culture medium, for example,aspects of the present invention permit performing an in situ qualitycheck of the sterility of the radiopharmaceutical. However, the accuracyof the volume of the product used with the growth media can greatlyimpact the results of the test. Accordingly, as shown in FIG. 9, a highperformance liquid chromatography (HPLC) load loop method may be used inconjunction with the sterility vial 450 to allow accurate, repeatablealiquots of liquid to be dispensed into the sterility vial 450.

The method involves attaching one end of the connector 412, for example,to a dispensing port 312 of the manifold tube 310. The distal end of theconnector 412 may be connected to a valve V1 which, as shown in FIG. 9,for example, may be a two-way valve that actuates between an A positionand a B position. In the A position, the valve V1 provides fluidcommunication between the connector 412 and a proximal end of a fixedvolume loop 454. In the B position, the valve V1 provides fluidcommunication between the connector 412 and an exit line 458, whichcould also be a catch vial, for example, and which may be by way of asecondary tube 456. A distal end of the fixed volume loop 454 may beconnected to a two-way valve V2 which actuates between a C position anda D position. In the C position, the valve V2 provides fluidcommunication between the fixed volume loop 454 and the sterility vial450. In the D position, the valve V2 provides fluid communicationbetween the fixed volume loop 454 and the exit line 458. The fixedvolume loop 454 may be a looped tube, for example, as shown in FIG. 9,which when completely filled provides an accurate volume of fluid,typically less than 1 ml. To begin the sterility test, the valve 320 isopened and the peristaltic pump 200 operated to provideradiopharmaceutical product into the connector 412. The valve V1 isplaced in the A position and the valve V2 is placed in the D position.Radiopharmaceutical product may be pumped through the loop 454 untilreaching the waste line, at which point the valve V1 is switched to theB position and then the valve V2 is switched to the C position.Pressurized gas from the gas line 275 may be used to then blow gasthrough the valve 320 in order to remove residual product to waste.After a predetermined interval, the valve V1 may be switched back to theA position to drive the fixed volume of radiopharmaceutical productcontained in the fixed volume loop 454 into the sterility vial 450.Because the sterility vial 450 contains a growth media, the technicianmay then directly determine the sterility of the sample of product.

As shown in FIGS. 1-3, the system 10 may also include a waste collectionsystem 600, comprising an optional vacuum pump 610 and a wastereceptacle 620. Another sterilization filter 630 may be provided toprevent any backflow contamination from entering the closed fill pathduring a dispensing operation.

As described above, a closed path system 10 may be formed that includesthe bulk product vial 100, the tube element 210 as mounted in theperistaltic pump 200, the dilution container 260, the sterilizationfilter 270, the dispensing manifold assembly 300, including the manifoldtubes 310 and valves 320, and the final product vials 400, all of whichmay be disposable elements that can be removed after each production runand easily and efficiently replaced with new elements for the nextproduction run. As shown in FIGS. 10 and 11, a sterile kit 500 may beprovided for each new compounding run of a radiopharmaceutical thatincludes one or more of the bulk product vial 100, the dilutioncontainer 260, pre-filled with the dilution solution, the filter 270,the manifold tubes 310 and valves 320, and the final product vials 400,including the vented fill caps 420. The kit 500 may come with certain orall of the components preassembled to allow for efficient set up of thesystem 10.

The kit 500 may be aseptically assembled inside a laminar flow hoodinside a clean room prior to packaging for delivery and use. The kitcomponents may be sterilized through a gamma radiation sterilizationtechnique, or where the final product vials 400 may be susceptible todamage from the gamma radiation, for example, steam sterilizationtechniques may be used. Accordingly, the kit components may arrivesterilized with some of the components already connected. The dilutioncontainer 260, sterility vial 450, final product vials 400, and ventedfill caps 420 for each sterility vial 450 and final product vial 400 mayrequire cleaning. Although the inside and/or contents of each of thecomponents may be sterile, the outside surfaces and, in particular, thesepta, or resealable membranes of the vials, may be sterilized withalcohol wipes prior to use in the kit. For example, the vented fill cap420 packages may be opened in the laminar flow hood, however, thepackages should be soaked in hydrogen peroxide or alcohol prior toplacement in the laminar flow hood. The vented fill caps 420 in thepackages are sterile and therefore do not require additionalsterilization upon being released from the packages when in the laminarflow hood.

As shown in FIG. 10, once sterilized in the hood, the dilution container260 and vials 400/450 may be connected to the other sterile kitcomponents. The dilution container 260 may be connected by inserting aneedle 262 through the dilution container's septum. A dilution tube 264may be connected to a distal end of the needle 262 and connected to themanifold tube 310 through a valve, as shown in FIG. 22, for example, byvalve 265. According to another aspect of the invention, the dilutiontube 264 may be configured to connect directly to one of the dispensingports 312, as shown with regard to the first port in FIG. 10. Ventedfill caps 420 may be mounted to the dispensing ports 312 directly, or byway of the connector tubes 412, for example, according to the number offinal product vials 400 desired and/or to accommodate the sterility vial450. The final product vials 400 and the sterility vial 450 may then beconnected to the corresponding vial caps 420, as appropriate. In thismanner, it may be preferable to connect the sterility vial 450 to thedispensing port 312 sequentially farthest from the pump 200 as comparedto the final product vials 400. In addition, if a mixture of vial sizesis being used in the system 10, larger final product vials 405 (see FIG.23) may be arranged to connect to dispensing ports 312 along with thesmaller final product vials 400 in any desired sequence with respect tothe pump 200.

FIG. 12 illustrates an exemplary vented fill cap 420. The vented fillcap 420 may include a spike 422 for inserting through an elastomericseptum 401 on the sealed final product vial 400 to provide fluidcommunication to an interior of the final product vial. FIG. 13illustrates an exemplary opening 402 left in the septum 401 of a sealedfinal product vial 400 immediately following removal of the spike 422.The length of time that the spike 422 remains puncturing the septum ofthe final product vial 400 can have an impact on the length of time ittakes the opening 402 in the elastomeric material to reset and resealfollowing removal of the vented fill cap 420 from the final product vial400.

FIGS. 14 and 15 illustrate a packaging device 520 that may providestability and protection for the vented fill caps 420 and the sealedfinal product vials 400 during shipping and handling of the kit 500. Inaddition, the packaging device 520 may provide an effective means forquickly and safely applying the vented fill caps 420 to the sealed finalproduct vials 400 while still in the sterile packaging of the kit 500.Thus, the vented fill caps 420 may be applied just prior to use so thatthe amount of time that the spike 422 punctures the septum 401 of thevials 400 may be minimized. Although described herein with reference tothe final product vial 400, the features described herein may also beused with the final product vial 405, the sterility vial 450, or anyother vial suitable for connection to a fill cap.

As shown in FIG. 14, each packaging device 520 may include a baseportion 522, which may be a generally flat substrate, for mounting avial containment portion 524 and a fill cap retention portion 526. Theillustrations in FIGS. 14 and 15 show five such packaging devices 520,which may be integrally connected on a single substrate material withperforations, for example, providing lines of demarcation for separationof one or more packaging devices 520, depending on the desiredconfiguration of the system 10. The vial containment portion 524 may beformed to be an open cylinder for slidably receiving the final productvial 400 through an open end distal from the end nearest the fill capretention portion 526. The vial containment portion 524 may have aninner diameter equal to or slightly smaller than the outer diameter ofthe final product vial 400 so that the vial 400 is substantially securedby a press fit arrangement with the vial containment portion 524. Inaccordance with other aspects of the present invention, any suitableretention device, such as internal tabs or an adhesive, may be used tosecure the final product vial 400 in the vial containment portion 524.An internal detent (not shown) may be provided to prevent the finalproduct vial 400 from sliding beyond a certain point into the vialcontainment portion 524 unless overcome by an application of forceagainst the exposed lower end of the final product vial 400.Accordingly, the final product vial 400 may be secured in apredetermined position relative to the vented fill cap 420 and, inparticular, the spike 422, during transport and handling of the kit 500.The fill cap retention portion 526 may include one or more cap retentiondevices 527, such as clips or clamps, for mounting and holding thevented fill cap 420 in a stable position against the base portion 522.As shown in FIG. 14, the vented fill cap 420 may be mounted in the fillcap retention portion 526 with the spike 422 shielded by an upperportion of the vial containment portion 524 to protect the kit 500 frompuncture during transport and handling, as well as to protect atechnician, for example, from injury during application of the ventedfill cap 420 onto the sealed final product vial 400. The packagingdevice 520 thus maintains the spike 422 of the vented fill cap 420protected and at a predetermined distance from the septum 401 of thefinal product vial 400 when in a storage configuration.

When ready for use, a technician may hold the packaging device 520, orapply pressure against the distal end of the vented fill cap 420, whileapplying an opposing pressure against the distal end of the finalproduct vial 400. As shown by the arrows in FIG. 14, force is appliedagainst the distal end of the final product vial 400 to overcome anyretention forces as a result of detents and/or retention devices inorder to slide the final product vial 400 toward the vented fill cap420. Vial guides 528 may be provided to extend between the vialcontainment portion 524 and the fill cap retention portion 526. The vialcontainment portion 524 and vial guides 528 guide the final product vial400 as it is pushed toward the vented fill cap 420 until the spike 422pierces the septum 401. The packaging device 520 is designed to beeasily accessible and actuated while remaining in the unopened sterilepackaging of the kit 500. Thus, piercing of the vial septum 401 may bedone just prior to opening the sterile packaging of the kit 500. Asshown in FIG. 15, the final product vial 400 with the vented fill cap420 attached may then be connected to one of the dispensing ports 312 ofthe manifold tube 310 for assembly into the system 10.

In accordance with yet other aspects of the present invention, FIGS. 16and 17 illustrate a second packaging device 530 that may be used in thekit 500. As shown in FIG. 16, each packaging device 530 may include avial containment portion 534 and a fill cap retention portion 536. Thefill cap retention portion 536 may include one or more cap retentiondevices 537, such as clips or clamps, for mounting and holding thevented fill cap 420 in a stable position. The vial containment portion534 may be a plurality of extension clips 538 integrally formed toextend from a lower portion of the fill cap retention portion 536. Theextension clips 538 may be configured to extend circumferentially aroundthe spike 422, wherein the distal ends of the extension clips 538 areconfigured to form a circle having an inner diameter equal to orslightly smaller than the outer diameter of the final product vial 400so that the vial 400 is substantially secured by a press fit arrangementwith the vial containment portion 534.

In accordance with other aspects of the present invention, any suitableretention device, including, as shown in FIG. 16, detent clips 539, maybe provided to secure the final product vial 400 in the vial containmentportion 534. The detent clips 539 may be formed to extend from the fillcap retention portion 536 and mate with a feature on the final productvial 400, such as a neck portion, for example. The detent clips 539 mayalso prevent the final product vial 400 from sliding beyond a certainpoint into the vial containment portion 534 unless overcome by anapplication of force against the exposed lower end of the final productvial 400. Thus, the final product vial 400 may be secured in apredetermined position relative to the vented fill cap 420 and, inparticular, the spike 422, during transport and handling of the kit 500.In addition, the spike 422 may be shielded by the extension clips 538and/or the detent clips 539 to protect the kit 500 from puncture duringtransport and handling as well as to protect a technician, for example,from injury during application of the vented fill cap 420 onto thesealed final product vial 400. The packaging device 530 maintains thespike 422 of the vented fill cap 420 protected and at a predetermineddistance from the septum 401 of the final product vial 400 when in astorage configuration.

When ready for use, a technician may hold the packaging device 530, orapply pressure against the distal end of the vented fill cap 420, whileapplying an opposing pressure against the distal end of the finalproduct vial 400. As shown by the arrows in the FIG. 16, force may beapplied against the distal end of the final product vial 400 to overcomeany retention forces as a result of detents and/or other retentiondevices in order to slide the final product vial 400 toward the ventedfill cap 420. The extension clips 538 and/or detent clips 539 may serveto guide the final product vial 400 as it is pushed toward the ventedfill cap 420 until the spike 422 pierces the septum 401. The packagingdevice 530 is designed to be easily accessible and actuated whileremaining in the unopened sterile packaging of the kit 500. Thus,piercing of the vial septum 401 may be done just prior to opening thesterile packaging of the kit 500. As shown in FIG. 17, the final productvial 400 with the vented fill cap 420 attached is ready to be connectedto one of the dispensing ports 312 of the manifold tube 310 for assemblyinto the system 10.

In accordance with yet other aspects of the present invention, FIGS.18-20 illustrate another packaging device 550 that may be used in thekit 500. As shown in FIG. 18, the packaging device 550 may include atray 555, which may be thermoformed from a plastic, or any othersuitable material. The tray 555 may be formed to have one or more vialcontainment portions 560 and fill cap retention portions 570.

The fill cap retention portion 570 may be a cavity formed in the trayand shaped to house the vented fill cap 420 in a stable position. Asshown in FIG. 18, the vented fill cap 420 may be provided with a capretention means 572. The cap retention means 572 may be configured toslidably receive and retain the product vial 400 when the product vial400 is physically forced towards the vented fill cap 420. The capretention means 572 may include, for example, a plurality of capretention arms 574 that extend from distal ends of a transverse capretention member 576 toward the product vial 400 contained in the vialcontainment portion 560. The fill cap retention portion 570 of the tray555 may be formed to have a wider transverse width than a transversewidth of the vial containment portion 560. The cap retention arms 574may be bent or flared toward a distal end so that the distal ends 575 ofthe cap retention arms 574 also have a wider transverse width than thetransverse width of the vial containment portion 560. In this manner,the vented fill cap 420 may be securely housed in the fill cap retentionportion 570 of the tray 555. The flared distal ends 575 of the capretention arms 574 prevent any substantial movement of the fill cap 420in a direction toward the product vial 400 by seating against atransitional surface 578 of the fill cap retention portion 570 where thefill cap retention portion 570 extends to be wider than the vialcontainment portion 560. Similarly, the transverse cap retention member576 may be configured to have a width wider than an upper fill cap slot580 formed in the tray 555. The transverse cap retention member 576 thusprevents from the vented fill cap 420 from substantial movement in adirection away from the product vial 400.

The vial containment portion 560 may be a partial-cylindrical cavityformed in the tray 555 to accept the product vial 400 in a press fitmanner, for example, to secure the product vial 400 in the vialcontainment portion 560. A lower surface 562 of the vial containmentportion may serve to seat the product vial 400 when in a storageposition. In accordance with other aspects of the present invention,detents or other similar retention devices may be provided, for example,to extend from the inner cylindrical wall of the vial containmentportion 560 to prevent the product vial 400 from any substantialmovement in the direction of the vented fill cap 420 during transportand/or handling. The final product vial 400 may thus be prevented fromsliding beyond a certain point into the vial containment portion 570unless overcome by an application of force against the exposed lower endof the final product vial 400. The final product vial 400 is thussecured in a predetermined position relative to the vented fill cap 420and, in particular, the spike 422, during transport and handling of thekit 500.

As shown in FIG. 18, the spike 422 may extend from a central portion ofthe retention member 576 to be positioned above the septum of theproduct vial 400. Because the product vial 400 and the vented fill cap420 are secured as described above, the spike 422 may be shielded by theretention arms 574 and the configuration of the tray 555 to protect thekit 500 from puncture during transport and handling, as well as toprotect a technician, for example, from injury during application of thevented fill cap 420 onto the sealed final product vial 400. Thepackaging device 550 maintains the spike 422 of the vented fill cap 420protected and at a predetermined distance from the septum 401 of thefinal product vial 400 when in a storage configuration.

In accordance with another aspect of the present invention, the tray 555may be configured to have a lower slot 584 extending away from the lowersurface 562 of the vial containment portion 560. The slot 584 may besized to allow a technician to insert a finger into the slot 584 forapplying a force against the bottom surface of the product vial 400.

When ready for use, a technician may hold the tray 555 of the packagingdevice 550 while applying pressure against the distal end of the finalproduct vial 400. As shown by the arrows in FIG. 18, force may beapplied against the distal end of the final product vial 400, forexample, by use of one or more thumbs or fingers in the slot 584, toovercome any retention forces as a result of the press fits, detentsand/or other retention devices in order to slide the final product vial400 toward the vented fill cap 420. Support ribs 586 may be provided toextend from the tray 555 to improve the ergonomic use and stabilizationof the tray 555 during the application of force.

As shown in FIG. 19, with the tray 555 resting on a flat surface, atechnician may use one or more thumbs, for example, to apply forceagainst the distal end of the final product vial 400 while stabilizingthe tray 555 with one or more fingers placed on the support ribs 586.The support ribs 586 may thus allow a more natural squeezing motion bythe technician while the final product vial 400 is pushed through thevial retention containment portion 560 toward the vented fill cap 420until the spike 422 pierces the septum and the vented fill cap 420 issecured to the product vial 400.

As shown in FIG. 20, in accordance with another aspect of the presentinvention, the cap retention arms 574 may be provided with a securingmechanism 577, such as a snap fit feature, to mate with a feature of theproduct vial 400, such as a cap, to further secure the product vial 400to the vented fill cap 420 during removal of the product vials 400 fromthe tray 555. Features such as small ribs, for example, may also beincorporated into the tray 555 to retain the vials 400 and spikes 422 inthe tray 555 should the packaging device 550 be inverted or otherwisesubjected to severe movements.

The packaging device 550 is designed to be easily accessible andactuated while remaining in the unopened sterile packaging of the kit500. Thus, piercing of the vial septum 401 may be done just prior toopening the sterile packaging of the kit 500. As shown in FIG. 20, thefinal product vials 400 with the vented fill caps 420 attached andconnected to the dispensing ports 312 of the manifold tube 310 are readyfor assembly into the system 10.

In accordance with another aspect of the present invention, as shown inFIG. 21, the sterile packaging of the kit 500 may be formed of aflexible, transparent material and with at least one integrated mitt 510to allow access to the kit components without opening the packaging. Thesterile packaging of the kit 500 may be configured to provide ampleinterior room when expanded to allow a technician to easily maneuver andmanipulate the components inside the packaging without removing thecomponents from the sterile kit environment.

FIG. 22 illustrates a vial fill process in accordance with aspects ofthe present invention. Once the radiopharmaceutical compound 110 hasbeen mixed with the sterile dilution solution from the dilutioncontainer 260, by way of reverse (i.e., counterclockwise) operation ofthe peristaltic pump 200, as described previously, and with the valves265 and 280 closed to the dilution container 260 and the pressurized gasline 275, the first valve 320 associated with the first final productvial 400 may be opened. In this manner, a closed path may be establishedto provide fluid communication from the interior of the bulk productvial 100 to the interior of the first final product vial 400. Thestepper motor 250 may then be controlled to operate the pump 200 in aforward (i.e., clockwise) direction in order to draw radiopharmaceuticalproduct from the bulk product vial 100 and push the product through thetube element 210, through the sterilization filter 270, through thedispensing port 312 associated with the first final product vial 400,and into the first final product vial 400. The amount of product to bedispensed in each vial 400 may be input through a software interfacethat is part of the control system 700, for example. In accordance withanother aspect of the present invention, the technician may observe afill amount in the vial 400 and manually control the pump and/or valvesto provide the desired amount. Once the desired amount of theradiopharmaceutical compound is filled in the first vial 400, theassociated valve 320 may be closed. If another dosage of theradiopharmaceutical is desired, the fill process may be repeated foreach successive vial 400 attached to a dispensing port 312.

FIG. 23 illustrates the ease with which different size vials may be usedwith the system 10. For example, if the final product vial 400 is astandard 10 ml vial, a 30 ml final product vial 405 may be attached toan appropriate dispensing port 312 for depositing a larger amount of theradiopharmaceutical. In this manner, the system 10 may be used to fillone or more vials of the same size and/or one or more vials of differingsizes. According to another aspect of the invention, as shown in FIG.23A, the connector tubes 412 may be preformed to provide a branchedconnection to more than one final product vial of differing sizes, 400and 405, for example. A technician may then select which size finalproduct vial is to be used with each corresponding dispensing port 312and remove the unnecessary final product vial 400 or 405 associated withthat dispensing port 312. When assembling the components in an asepticenvironment, as described below, a technician may use thermal scissors,for example, to cut one of the branches and provide a closed fluid pathto the correct size final product vial 400 or 405.

In accordance with another aspect of the invention, if vented fill caps420 are not being used, for example, each vial 400 or 405 may beevacuated prior to being filled. The vacuum pump 610 may be used toapply a vacuum pressure to the interior of each of the vials 400.Because the system is a closed system, opening the valve 320 associatedwith a particular vial 400, as shown in FIG. 24 with respect to thetenth vial 400 (from closest to the pump 200 to farthest), and operatingthe vacuum pump 610 will evacuate the air from the interior of the vial400. Closing the valve 320 and sequentially performing the sameoperation may evacuate the interior of each vial 400 as well as theinterior of the closed path through to the pump 200, which may be lockedto prevent rotation by way of the negative pressure. Thus, the fillprocess may be enhanced and the vials filled without the need to providea separate venting means.

Furthermore, another aspect according to the present invention includesusing the pressured gas line 275 to create a positive pressure in theinterior of the vial 400 after the vial 400 is filled with aradiopharmaceutical compound. As shown in FIG. 25, for example, thevalve 280 may be opened while the valve 320 to the filled vial 400remains open. Thus, the pressured gas may flow into the vial 400. Apositive pressure may be created in the vial 400 so that when the vial400 is removed from the system 10, which may be by pulling the vial 400off of the dispensing port 312, the positive internal pressure willprevent any foreign contaminants from entering the interior of the vial400.

The process disclosed above may be continued until all of the vials 400,for example, are filled, as shown in FIG. 26. The filled vials 400 maythen be removed from the system, as shown in FIG. 27, by manual orautomated means, for subsequent delivery in shielded vial containers toa practitioner for use in an imaging procedure, for example.

FIG. 28 illustrates a process in which the disposable portions of thesystem 10 may be flushed once the vials 400 have been released for use.For example, valve 265 may be opened and the stepper motor 250 operatedto run the pump 200 in reverse so that any remaining dilution solutionmay flush through the tube element 210 and into the bulk product vial100. The valve 265 may then be closed, the stepper motor 250 operated torun in forward, and/or the vacuum pump 610 turned on to create a suctionforce in order to complete the flushing by pulling the flush solutionfrom the bulk product vial 100, and pushing/pulling the flush solutionthrough the tube element 210, the filter 270, the manifold tubes 310,the second filter 630, and into a waste receptacle 620. Thus, much ofthe residual radioactivity may be effectively removed from thedisposable elements, further protecting the technicians from exposureduring the removal and/or replacement of the disposable elements. Thewaste receptacle 620 may be provided in a separately shielded enclosurefor removal and disposition.

FIG. 29 illustrates the closed fill vial system 10 as it may be providedin a shielded, or “hot cell” environment. To protect the technicianscompounding and preparing the radiopharmaceuticals for distribution, theclosed fill vial system 10 may be provided as a microcell structure inthe interior of a hot cell 800, which may be a lead lined enclosure, forexample. Although the closed fill vial system 10 will protect theradiopharmaceutical from contamination during dispensing, a particlecounter 810 and/or an air filter 820 may also be provided to furthermonitor and provide a clean air environment within the hot cell 800.

As disclosed above, aspects of the dispensing operation may becontrolled by manually turning on and off the pump 200, and manuallycontrolling the valves 320, for example. Each vial 400 may be providedwith an amount of the dispensed product via visual observation. However,as discussed above, an exemplary closed fill vial system 10 may includea control system 700 to provide automation to the closed fill vialsystem 10, further reducing the need of a technician, for example, to bephysically engaged with the system 10 at times when the radionuclide maybe most active.

FIG. 30 shows various features of an example computer system for use inconjunction with aspects of the control system 700 of the presentinvention. Although computer monitoring and/or control of the vialfilling process, or the in-situ filter integrity testing, for example,may be automated, the computer system may also be accessed by a user1101 to control and/or access the equipment comprising the closed fillvial system 10, input or access data to control and/or monitor variousparameter, monitor status of the equipment and/or process, and/or toperform other steps or acts in accordance with aspects of the presentinvention, such as by using software and other computer features locatedon a server or other network device 1106. Access occurs, for example,via a terminal 1102, network (e.g., the Internet) 1110, and couplings1111, 1113. Access to the control equipment of the system 10, forexample, may occur via coupling 1114. The terminal 1102 may comprise,for example, a personal computer (PC), minicomputer, mainframe computer,microcomputer, telephone device, personal digital assistant (PDA), orother device having a processor and input capability. The server 1106may comprise, for example, a PC, minicomputer, mainframe computer,microcomputer, or other device having a processor and a repository fordata or that is capable of accessing a repository of data. Couplings1111, 1113 and 1114 may include wired, wireless, or fiberoptic links.

Aspects of the present invention may be implemented using hardware,software or a combination thereof and may be implemented in one or morecomputer systems or other processing systems. In one variation, theinvention is directed toward one or more computer systems capable ofcarrying out the functionality described herein. An example of such acomputer system 1200 is shown in FIG. 31.

Computer system 1200 includes one or more processors, such as processor1204. The processor 1204 is connected to a communication infrastructure1206 (e.g., a communications bus, cross-over bar, or network). Varioussoftware variations are described in terms of this exemplary computersystem. After reading this description, it will become apparent to aperson skilled in the relevant art(s) how to implement aspects of theinvention using other computer systems and/or architectures.

Computer system 1200 can include a display interface 1202 that forwardsgraphics, text, and other data from the communication infrastructure1206 (or from a frame buffer not shown) for display on the display unit1230. Computer system 1200 also includes a main memory 1208, preferablyrandom access memory (RAM), and may also include a secondary memory1210. The secondary memory 1210 may include, for example, a hard diskdrive 1212 and/or a removable storage drive 1214, representing a floppydisk drive, a magnetic tape drive, an optical disk drive, etc. Theremovable storage drive 1214 reads from and/or writes to a removablestorage unit 1218 in a well-known manner. Removable storage unit 1218,represents a floppy disk, magnetic tape, optical disk, etc., which isread by and written to removable storage drive 1214. As will beappreciated, the removable storage unit 1218 includes a computer usablestorage medium having stored therein computer software and/or data.

In alternative variations, secondary memory 1210 may include othersimilar devices for allowing computer programs or other instructions tobe loaded into computer system 1200. Such devices may include, forexample, a removable storage unit 1222 and an interface 1220. Examplesof such may include a program cartridge and cartridge interface (such asthat found in video game devices), a removable memory chip (such as anerasable programmable read only memory (EPROM), or programmable readonly memory (PROM)) and associated socket, and other removable storageunits 1222 and interfaces 1220, which allow software and data to betransferred from the removable storage unit 1222 to computer system1200.

Computer system 1200 may also include a communications interface 1224.Communications interface 1224 allows software and data to be transferredbetween computer system 1200 and external devices. Examples ofcommunications interface 1224 may include a modem, a network interface(such as an Ethernet card), a communications port, a Personal ComputerMemory Card International Association (PCMCIA) slot and card, etc.Software and data transferred via communications interface 1224 are inthe form of signals 1228, which may be electronic, electromagnetic,optical or other signals capable of being received by communicationsinterface 1224. These signals 1228 are provided to communicationsinterface 1224 via a communications path (e.g., channel) 1226. This path1226 carries signals 1228 and may be implemented using wire or cable,fiber optics, a telephone line, a cellular link, a radio frequency (RF)link and/or other communications channels. In this document, the terms“computer program medium” and “computer usable medium” are used to refergenerally to media such as a removable storage drive 1214, a hard diskinstalled in hard disk drive 1212, and signals 1228. These computerprogram products provide software to the computer system 1200. Aspectsof the invention are directed to such computer program products.

Computer programs (also referred to as computer control logic) arestored in main memory 1208 and/or secondary memory 1210. Computerprograms may also be received via communications interface 1224. Suchcomputer programs, when executed, enable the computer system 1200 toperform the features of the present invention, as discussed herein. Inparticular, the computer programs, when executed, enable the processor1204 to perform aspects of the present invention via the control system700. Accordingly, such computer programs represent controllers of thecomputer system 1200.

In a variation where aspects of the invention are implemented usingsoftware, the software may be stored in a computer program product andloaded into computer system 1200 using removable storage drive 1214,hard drive 1212, or communications interface 1224. The control logic(software), when executed by the processor 1204, causes the processor1204 to perform various aspects of the invention as described herein. Inanother variation, aspects of the invention are implemented primarily inhardware using, for example, hardware components, such as applicationspecific integrated circuits (ASICs). Implementation of the hardwarestate machine so as to perform the functions described herein will beapparent to persons skilled in the relevant art(s).

FIG. 32 is an exemplary wireframe diagram of a display page for asoftware interface that may be used, for example, with the computersystem 1200 described above, in accordance with aspects of the presentinvention. The software may be developed as part of the control system700 for the closed fill vial system 10, and once validated, may beaccess controlled and monitored to ensure the integrity of themanufacturing process when implemented via the software interface. Asshown in FIG. 32, the software interface may provide a graphicaldepiction of various aspects of the system and a real-time view ofvarious settings, parameters, and functional attributes. Various userinterface feedback mechanisms for operation and control of the closedfill vial system 10 may be provided. For example, an “unstick” pumppushbutton control 1402 may be provided. If the user selects the control1402, by clicking on the graphical display of the button with the mousecursor, for example, the control system 700 may send a signal to thepump 200 to temporarily alternate between operating in a forwarddirection and operating in a reverse direction to unlock what may appearto be a locked pump 200. Various inputs may be provided to ensure theproper dosage of a radionuclide in the final product vial 400 to bedelivered for use in a procedure. For example, the user may input thedilution volume 1410 of the dilution container 260, which may be acertain number of mL of sterile water, for example. Another input mayinclude, Activity at Calibration Time 1412, which is the amount ofradionuclide activity, measured in millicuries (mCi), that must beavailable in the bulk product vial 100 at some future time, perhaps five(5) hours later, to ensure a proper radionuclide level will be availablefor dilution and distribution, recognizing that the half-life of theradionuclide may be 110 minutes. Thus, by knowing the Activity atCalibration Time 1412 may provide the system a mechanism for determiningan initial amount of radionuclide product to be deposited in the bulkproduct vial 100. Another input may include Activity Concentration 1414,which is the desired amount of radionuclide activity for a particularvolume of product to be delivered in a particular dose (mCi/mL). Thus,if the goal is 20 mCi/mL, for example, for a particular dosage, and theradiopharmaceutical product 110 initially delivered to the bulk productvial 100 measures 5000 mCi/17 mL, the product may be diluted to achievethe desired result, taking into account the Activity at Calibration Timediscussed above. Other inputs may include a QC Syringe Volume 1416,which may provided the amount of product to be delivered to a qualitycheck syringe or vial, and a Number of 30 mL vials 1418, for example, tocalibrate the amount of final radiopharmaceutical product that must beproduced and distributed. Once all of the inputs are entered, the usermay activate the control system 700 to automatically run the entire fillsequence from beginning to end, for example, by using the cursor toclick on a Dispense Product control 1420. Although described herein asbeing used to automate the entire system 10, the software interface andcontrol system 700 may be configured to provide single use control ofvarious functions of the system 10, such as activation of a fillsequence for a single final product vial 400 or a sterility vial 450,for example.

In accordance with yet other aspects of the present invention, as shownin FIGS. 33 and 34, the frame 40 of the system 10 may be configured toincorporate the manifold tubes 310 in a vertical arrangement and mayinclude a pump mounting bracket 42 for mounting one or more peristalticpumps 200. A vial bracket 44 may be attached to the frame 40 formounting the bulk product vial 100 to the system 10.

FIG. 35 illustrates another view of an exemplary vial bracket 44. Thevial bracket 44 may be configured to seat the bulk product vial 100 atan angle and have an orienting feature 45 for mating with an orientingfeature 101 of the bulk product vial 100, such as a specificallyconfigured top or a fitting for the top, for example, to quickly andefficiently allow a technician to align and seat the bulk product vial100 in the vial bracket 44 according to a specific orientation. The bulkproduct vial 100 may be provided with an aspirating needle 144 or a diptube, for example, configured to have an opening positioned at or nearthe lowest internal point of the tilted bulk product vial 100. The angleof the bulk product vial 100 and the specific orientation of theaspirating needle or dip tube, may thus work with gravity to ensurewithdrawal of substantially the entire product contained in the bulkproduct vial 100.

In accordance with yet another aspect of the present invention, as shownin FIG. 36, the vial bracket 44 may be incorporated onto a precisionscale 46 for mounting the bulk product vial 100 while providing theability to measure a precise volume of product received into the bulkproduct vial 100. For example, in order to calibrate the peristalticpump 200, the pump 200 may be operated to draw a certain amount of adilution solution from the dilution container 260 and pump the dilutionsolution into the bulk product vial 100. By knowing the specific gravityof the dilution solution, and by measuring the mass of the solutiondelivered into the bulk product vial 100 using the precision scale 46,the volume of delivered solution can be derived and compared to theexpected volume delivered for a certain number of revolutions of thestepper motor 250 for a tube of known internal dimensions. The precisionscale 46 may thus be used to calibrate the pump 200 to compensate forvarying flow characteristics that may occur during different runs of thesystem 10.

For example, slight differences in the internal diameters of theperistaltic tubing used in the disposable assemblies of the system 10may result in a different volume of product being processed through theperistaltic pump 200 for the same number of revolutions of the steppermotor 250. Calibration of the pump 200, as described above, may thusprovide a means for correcting or adjusting the baseline data in orderto permit a more precise metering of the product into, for example, thefinal product vials 400 and 405.

As shown in FIG. 36, the system 10 may incorporate a concentration,activity, and volume (CAV) sensor 1500, similar to the CAV sensordescribed in U.S. Provisional patent application Ser. No. 61/508,402entitled “Radiopharmaceutical CZT Sensor and Apparatus”, filed Jul. 15,2011, the entirety of which is incorporated herein by reference. The CAVsensor 1500 is an apparatus for detecting radionuclide content andactivity in a volume of material. The CAV sensor 1500 may include a CAVcontainer 1502 for receiving the radiopharmaceutical product 110directly from the chemistry synthesis unit (CSU), for example, and atleast one gamma ray detector 1504. As shown in FIG. 33, the CAVcontainer 1502 (shown apart from the full CAV sensor 1500) may beconnected to the bulk product vial 100 by way of a tube element 211. Thetube element 211 provides fluid communication between the interior ofthe CAV container 1502 and the interior of the bulk product vial 100 andmay be routed through a second peristaltic pump 201 for controlling afluid flow in the tube element 211.

The CAV sensor 1500 may determine the volume, activity and concentrationof the radiopharmaceutical product 110 received into the CAV container1502. The information from the CAV sensor 1500 may be automaticallyprovided to the control system 700, or the information may be read fromthe CAV sensor 1500 by a technician, for example, and manually inputinto the control system 700 prior to initiation of the automated vialfill process.

FIG. 37 is a schematic to further illustrate a closed vial fill system10 incorporating a CAV sensor 1500. The radiopharmaceutical product 110may be delivered from the synthesizing unit directly to the CAVcontainer 1502. The CAV sensor 1500 records the concentration, activity,and/or volume components of the radiopharmaceutical product 110. Oncethe desired parameters have been measured by the CAV sensor 1500, theperistaltic pump 201 may be used to draw the entire volume of theradiopharmaceutical product 110 from the CAV container 1502 for depositinto the bulk product vial 100. As described above in detail, theperistaltic pump 200 may then be used to draw a dilution solution fromthe dilution container 260 to dilute the radiopharmaceutical product 110to desired levels of concentration and activity in accordance with themeasurements recorded by the CAV sensor 1500. The diluted product maythen be used to fill the final product vials 400, 405, the sterilityvial 450, and/or the quality check syringes, for example, aspre-programmed in the control system 700.

FIGS. 38-65 are a series of schematic diagrams to illustrate exemplaryaspects of a closed vial fill system 10 incorporating a CAV sensor 1500,a single peristaltic pump 200, and a method of using the closed vialfill system 10 in conjunction with a computer system 1200 for usercontrol of the control system 700. The illustration discussedhereinafter begins once the disposable components of the system 10 havebeen installed as described previously.

To begin, a user may be required to logon to the computer system 1200 inorder to gain access to the control system 700. Once the usersuccessfully enters the user's login information, the user may berequested to select a particular closed vial fill system 10, if multiplesystems may be used in conjunction for different runs of aradiopharmaceutical product. For example, the user may be requested toselect either Unit 1 or Unit 2. The user selects which unit to use andmay be prompted to indicate that the disposable components have beensuccessfully installed for that particular unit. If the user confirmsthe installation of the disposable components onto the system 10, theuser may begin the process of automated fill by choosing to firstcalibrate the pump.

As shown in FIG. 38, when the user selects to calibrate the pump, theperistaltic pump 200 may be controlled to operate in a counterclockwisedirection, for example, to pull a predetermined amount of dilutionsolution from the dilution container 260. The dilution container 260 maybe integrated into the system 10, preferably between the peristalticpump 200 and the dispensing manifold assembly 300, by way of the valve265. The valve 265 may be a three-port solenoid valve, a diverter valve,or a stopcock valve, for example, and provide closed fluid communicationbetween the peristaltic pump 200 and the dispensing manifold assembly300 when selectively actuated to a first position, and closed fluidcommunication between the dilution container 260 and the peristalticpump 200 when selectively actuated to a second position. Thus, the valve265 is actuated to be in the second position and a fluid flow meter maybe used to calibrate the amount of dilution solution that flows from thedilution container 260 into the bulk product container 100 inassociation with the step motor revolutions of the peristaltic pump 200.

According to another aspect of the present invention, the bulk productvial 100 may be situated on a precision scale 46, in which the volume ofsolution being supplied to the bulk product container can be determinedbased on the measured mass of the solution. The volume may then becompared with the expected volume based on a set of predetermined flowcharacteristics of the peristaltic pump 200 and the associatedperistaltic tubing, and the peristaltic pump 200 may be calibratedaccordingly. As shown in FIG. 39, with the peristaltic pump 200 thuscalibrated, the pump 200 may be controlled to operate in the oppositedirection, e.g. clockwise, and the valve 265 controlled to be in thefirst position in order to pump the dilution solution from the bulkproduct vial 100 through the dispensing manifold assembly 300 and intothe waste receptacle 620, for example.

FIGS. 40-42 illustrate a purge process that may be initiated followingthe pump calibration. As shown in FIG. 40, the purge gas, preferablypressurized nitrogen, may be directed through a line 570 into the bulkproduct vial 100. With the peristaltic pump 200 operating in a clockwisedirection, for example, the valve 265 may be actuated to direct thepurge gas through the dispensing manifold assembly 300. As shown in FIG.41, the peristaltic pump 200 may then be operated in the reversedirection and the purge gas directed in a reverse direction, firstthrough the CAV container 1502 and then to the bulk product vial 100,where it may be vented to the atmosphere. As shown in FIG. 42, theperistaltic pump 200 may be reversed yet again to purge each of thevials, preferably in order, with the purge gas being vented to theatmosphere through each of the vented vial fill caps 420. Finally, ifneeded, the input line 565 from the synthesis unit may be purged usingpurge gas supplied from the synthesis unit.

As shown in FIG. 43, following the purging of the disposable componentswith nitrogen, the concentrated radiopharmaceutical product 110 may bereceived into the CAV container 1502 from the synthesis unit through theinput line 565. As shown in FIG. 44, once the concentrated product 110has been completely received, the input line 565 may be purged withnitrogen to clear the line. With the concentrated radiopharmaceuticalproduct 110 in the CAV container 1502, the user may select to measurethe activity in the CAV container 1502. The control system 700 may thenactivate the CAV sensor 1500 to obtain desired parameters, such asactivity and concentration of the concentrated radiopharmaceuticalproduct 110.

As shown in FIG. 45, the CAV container 1502 may be connected to athree-way valve 266, which may be one of the valves of the dispensingmanifold assembly 300. The valve 266 may be actuated to a first positionin which a fluid flow path is opened between the CAV container 1502 andthe bulk product vial 100. When actuated to a second position, the valvemay shut off fluid flow to the CAV container 502 and allow unimpeded,substantially laminar fluid flow through the manifold tube 310. Afterthe CAV sensor 1500 has obtained the desired parameters, as shown inFIG. 45, and with the valve 266 actuated to the first position, theperistaltic pump 200 may be actuated to operate in reverse to transferthe concentrated radiopharmaceutical product 110 from the CAV container1502 to the bulk product vial 100. As shown in FIG. 46, with theentirety of the concentrated product 110 transferred to the bulk productvial 100, the mass, and hence volume, of the concentrated product 110may be determined, such as by using the precision scale 46 discussedabove, for example. In the case where the volume of the concentratedproduct 110 is determined by the CAV sensor 1500, the precision scale 46may serve as a quality check to verify the accuracy of the CAV sensorvolume measurement.

To begin the automated vial fill process, the user may be requested toperform a “Set-Up” task, wherein the user inputs a dilution solutionvolume and the vial fill volumes for each of the vials attached to thedispensing manifold assembly 300. Once complete, the user may select a“Start Fill” command, for example, to begin the automated fill process.As shown in FIG. 47, the control system 700 may actuate the peristalticpump 200 to operate in reverse while opening the valve 265 to allow apredetermined volume of the dilution solution, as set by the user, toflow from the dilution container 260 into the bulk product vial 100.

As shown in FIG. 48, the valve 265 may be closed to the dilutioncontainer 260 and nitrogen forced through the system to purge anyremaining dilution solution from the peristaltic tubing leading to thebulk product vial 100. In doing so, nitrogen may be bubbled through thediluted radiopharmaceutical product in the bulk product vial 100 beforeexiting through the vent filter, for example, further helping to mix thediluted product.

In accordance with another aspect of the present invention, rather thanusing nitrogen to clear the lines, for example, the peristaltic pump 200may be operated to return a small amount of the diluted product back tothe CAV container 1502. The pump 200 may then be reversed again toreturn the small amount of diluted product from the CAV container 1502back to the bulk product vial 100. Thus, any small amount of liquid thatmay be left remaining in the CAV container 1502 or the lines from theCAV container 1502 to the dispensing manifold assembly 300 will bediluted, rather than concentrated.

As shown in FIGS. 49 and 50, the control system 700 may operate the pump200 to fill the manifold tubes 310 with the diluted product up to thefurthest final product vial 400 or 405. The control system 700 may thenbegin filling the vials from right to left, for example, starting withthe sterility vial 450, followed by the quality check vial 482, and theneach of the final product vials 400 and 405. Although described in aparticular order herein, the control system 700 may be configuredthrough user input via the computer system 1200 to fill the vials in anyorder.

As shown in FIG. 51, excess diluted product in the bulk product vial100, along with excess diluted product in the peristaltic tubing and themanifold tubes 310, for example, may be purged using nitrogen andcollected in a final product vial 405 connected to the manifold tube 310furthest from the pump 200. As shown in FIGS. 52-55, the fill processmay be completed by purging any diluted product remaining in the linesto the vials, for example, preferably beginning with the vial farthestaway from the pump and continuing with each closer vial until all of thevials have been purged.

In accordance with another aspect of the present invention, as shown inFIG. 56, a rinse, such as water, or any other suitable cleansing fluid,may be provided from the synthesis unit to further clean the disposablesof possible radioactive residue. The rinse may be delivered from thesynthesis unit through the line 565 and deposited into the CAV container1502. Once the rinse is delivered to the CAV container 1502, the usermay select a “Start Rinse” command, for example, to begin the rinseprocess. As shown in FIGS. 57 and 58, the control system 700 may actuatethe peristaltic pump 200 to operate in a reverse direction in order totransfer the rinse from the CAV container 1502 to the bulk product vial100. As shown in FIG. 59, with the CAV container 1502 and the fluidlines between the CAV container 1502 and the bulk product vial 100 thusrinsed, the peristaltic pump 200 may be operated to draw the rinse fromthe bulk product vial 100 and force the rinse through the manifold tubes310 to the waste receptacle (not shown). In accordance with yet anotheraspect of the present invention, as shown in FIG. 60, the peristalticpump 200 may continue to operate in order to draw in atmospheric air,for example, through the vented bulk product vial 100 and pump the airthrough the lines and the manifold tubes 310 until all of the rinse isdeposited into the waste receptacle.

In accordance with yet another aspect of the present invention, as shownin FIGS. 61-65, the remaining dilution solution in the dilutioncontainer 260 may be used to perform another rinse of the disposablecomponents. As shown in FIG. 61, the valve 265 may be opened and theperistaltic pump 200 operated to pull the remaining dilution solutionfrom the dilution container 260 into the bulk product vial 100. Once theremaining dilution solution is in the bulk product vial 100, as shown inFIG. 62, the valve 265 may be closed to the dilution container 260, thevalve 266 may be opened to allow fluid communication between the bulkproduct vial 100 and the CAV container 1502, and the peristaltic pump200 may be operated in reverse to pull the dilution solution from thebulk product vial 100 and pump the dilution solution into the CAVcontainer 1502.

As shown in FIG. 63, once the dilution solution has been pumped into theCAV container 1502, the process may be reversed by reversing thedirection of the pump 200 and the dilution solution transferred back tothe bulk product vial 100 from the CAV container 1502. With the fluidpath between the bulk product vial 100 and the CAV container 1502 thusrinsed, the valves 265 and 266 may be opened to allow fluid flow throughthe manifold tubes 310. As shown in FIG. 64, the dilution solution maythen be pumped out of the bulk product vial 100 and through the manifoldtubes 310 to the waste receptacle (not shown). As shown in FIG. 65, theperistaltic pump 200 may continue to operate in order to draw inatmospheric air, for example, through the vented bulk product vial 100and pump the air through the system until all or substantially all ofthe dilution solution is forced from the manifold tubes 310 and into thewaste receptacle (not shown).

As described previously, the vials may then be removed from the system10 for transport in a shielded container to the appropriate location fortesting and/or use in a procedure. The disposable components of thesystem 10 may be removed and discarded according to the proper protocoland the system prepared for another run.

The previous description is provided to enable any person skilled in theart to practice the various exemplary implementations described herein.Various modifications to these variations will be readily apparent tothose skilled in the art, and the generic principles defined herein maybe applied to other implementations. All structural and functionalequivalents to the elements of the various illustrious examplesdescribed throughout this disclosure that are known or later come to beknown to those of ordinary skill in the art are expressly incorporatedherein by reference.

The invention claimed is:
 1. A sterilized kit comprising: a finalproduct vial comprising a septum; a fill cap comprising a spike capableof piercing the septum, wherein the fill cap is capable of beingremovably coupled to the final product vial; a tray comprising a vialcontainment portion sized to receive the final product vial and a capretention portion sized to receive the fill cap; and sterile packagingenclosing the final product vial, fill cap, and tray, wherein the spikeis capable of piercing the septum when the sterile packaging isunopened.
 2. The sterilized kit of claim 1, wherein the sterilepackaging is a flexible material.
 3. The sterilized kit of claim 1,wherein the fill cap comprises cap retention arms to secure the finalproduct vial to the fill cap.
 4. The sterilized kit of claim 1, whereinthe final product vial is secured in the vial containment portion of thetray by a press fit.
 5. The sterilized kit of claim 1, wherein the vialcontainment portion of the tray prevents substantial movement of thefinal product vial toward the fill cap during shipping and handling ofthe sterilized kit.
 6. The sterilized kit of claim 1, wherein the traymaintains the spike of the fill cap at a predetermined distance from thefinal product vial.
 7. The sterilized kit of claim 1, wherein the vialcontainment portion is cylindrical with an open end.
 8. The sterilizedkit of claim 1, wherein the tray further comprises a base portion, andwherein the cap retention portion and the vial containment portion aremounted to the base portion.
 9. The sterilized kit of claim 1, whereinthe fill cap is connected to a bulk product vial via a dispensingmanifold assembly.
 10. The sterilized kit of claim 1, wherein the fillcap is a vented fill cap.
 11. A method of using a sterilized kit, themethod comprising: obtaining a sterilized kit in a storageconfiguration, the sterilized kit comprising: a final product vialcomprising a septum; a fill cap comprising a spike; a tray comprising avial containment portion sized to receive the final product vial and acap retention portion sized to receive the fill cap; and sterilepackaging enclosing the final product vial, fill cap, and tray; whereinthe spike is spaced from the septum in the storage configuration;piercing the septum of the final product vial with the spike on the fillcap, thereby creating an opening in the septum; opening the sterilepackaging after piercing the septum; adding a product to the finalproduct vial through the spike on the fill cap; and removing the spikefrom the septum, thereby resealing the opening in the septum.
 12. Themethod of claim 11, wherein the step of piercing the septum comprisesmoving the final product vial toward the fill cap.
 13. The method ofclaim 12, wherein the tray guides the final product vial when moving thefinal product vial toward the fill cap.
 14. The method of claim 11,further comprising a step of coupling the final product vial to the fillcap.
 15. The method of claim 11, wherein the sterilized kit is in astorage configuration during the step of providing the sterilized kit,and wherein the spike does not pierce the septum in the storageconfiguration.
 16. The method of claim 14, further comprising a step ofremoving the final product vial and the fill cap from the tray while thefinal product vial is coupled to the fill cap.
 17. A sterilized kitcomprising: a bulk product vial; a dispensing manifold assembly coupledwith the bulk product vial; a final product vial comprising a septum; afill cap coupled to the dispensing manifold assembly, wherein the fillcap is removably coupleable to the final product vial and comprises aspike capable of piercing the septum of the final product vial; a trayhaving a vial containment portion sized to receive a final product vialand a cap retention portion sized to receive the fill cap; and sterilepackaging enclosing the final product vial, fill cap, and tray, whereinthe spike is capable of piercing the septum when the sterile packagingis unopened, and wherein the final product vial and the fill cap areremoveable from the tray while coupled to one another.
 18. Thesterilized kit of claim 17, further comprising a dilution containercapable of communicating with the bulk product vial.
 19. The sterilizedkit of claim 17, wherein the final product vial is one of a plurality offinal product vials and the fill cap is one of a plurality of fill caps.20. The sterilized kit of claim 19, wherein the tray comprises aplurality of vial containment portions, each vial containment portionsized to receive one of the plurality of final product vials.